PP018. Does altitude affect the placental renin angiotensin system (RAS) in pre-eclampsia (PE)?

Abstract

We have previously shown the activation of placental RAS in high altitude normotensive (NT) pregnancies [1], presumably related to hypoxia during placental development. PE incidence is increased at high altitude; hypoxia-reoxygenation injury contributes to the elevated oxidative stress seen in this condition. Binding of Angiotensin II to its type I receptor (AT1R) increases generation of reactive oxygen species and we have shown an increase in AT1R in PE [2]. Therefore we investigated whether the RAS is further augmented in PE at high altitudes. Biopsies were collected, with informed, written consent, from NT and PE women (ISSHP guidelines) at sea-level (UK) and high altitude, 3100m (Leadville, Colorado) immediately after vaginal delivery or elective non-laboured Caesarean section. mRNA expression of the RAS components (angiotensinogen (AGT), prorenin, prorenin receptor, AT1R and angiotensin type 2 receptor) was determined by qRT-PCR and normalised to 3 stably-expressed housekeeping genes using geNorm. Protein expression was semi-quantitatively assessed by immunohistochemistry (H score) and compared between groups (Mann Whitney U test). mRNA expression of all RAS components was unaffected by altitude in NT, but significantly lower for all in PE (P=0.026-<0.0001). However, in NT, protein expression of all components except AGT was significantly increased at altitude (P=0.037-<0.001). Protein expression of AGT and AT1R was also increased in altitude PE (P<0.004 for both). We have shown the placental RAS to be activated at altitude, with apparent differences in transcription/translation. Hypoxia-inducible transcription factors such as HIF-1 enhance transcription and translation of many genes encoding "rescue" proteins; this might explain the effects of altitude in NTs. HIF-1 is increased in PE, which might allow increased protein expression at altitude in spite of lower mRNA.